5UEZ

BRD4_BD2_A-1342843

5UEZ の概要

• エントリーDOI: 10.2210/pdb5uez/pdb
• 関連するPDBエントリー: 5UEO 5UEP 5UEQ 5UER 5UES 5UET 5UEU 5UEV 5UEW 5UEX 5UEY 5UF0
• 分子名称: Bromodomain-containing protein 4, 5-methoxy-2-methyl-6-(2-phenoxyphenyl)pyridazin-3(2H)-one (3 entities in total)
• 機能のキーワード: signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13115.26

構造登録者

Park, C.H. (登録日: 2017-01-03, 公開日: 2017-05-10, 最終更新日: 2024-04-03)

主引用文献

Wang, L.,Pratt, J.K.,Soltwedel, T.,Sheppard, G.S.,Fidanze, S.D.,Liu, D.,Hasvold, L.A.,Mantei, R.A.,Holms, J.H.,McClellan, W.J.,Wendt, M.D.,Wada, C.,Frey, R.,Hansen, T.M.,Hubbard, R.,Park, C.H.,Li, L.,Magoc, T.J.,Albert, D.H.,Lin, X.,Warder, S.E.,Kovar, P.,Huang, X.,Wilcox, D.,Wang, R.,Rajaraman, G.,Petros, A.M.,Hutchins, C.W.,Panchal, S.C.,Sun, C.,Elmore, S.W.,Shen, Y.,Kati, W.M.,McDaniel, K.F.
Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.
J. Med. Chem., 60:3828-3850, 2017

PubMed Abstract: Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

PubMed: 28368119
DOI: 10.1021/acs.jmedchem.7b00017

実験手法

X-RAY DIFFRACTION (1.51 Å)